scholarly journals Deregulated Stat3 signaling dissociates pulmonary inflammation from emphysema in gp130 mutant mice

2012 ◽  
Vol 302 (7) ◽  
pp. L627-L639 ◽  
Author(s):  
Saleela M. Ruwanpura ◽  
Louise McLeod ◽  
Alistair Miller ◽  
Jessica Jones ◽  
Ross Vlahos ◽  
...  
Keyword(s):  
Lung Tissue ◽  
Lung Inflammation ◽  
Human Lung ◽  
Pulmonary Inflammation ◽  
Airflow Obstruction ◽  
Chronic Obstructive ◽  
Alveolar Cells ◽  
Human Lung Tissue ◽  
Stat3 Signaling

Interleukin (IL)-6 is a potent immunomodulatory cytokine that is associated with emphysema, a major component of chronic obstructive pulmonary disease (COPD). IL-6 signaling via the gp130 coreceptor is coupled to multiple signaling pathways, especially the latent transcription factor signal transducer and activator of transcription (Stat)3. However, the pathological role of endogenous gp130-dependent Stat3 activation in emphysema is ill defined. To elucidate the role of the IL-6/gp130/Stat3 signaling axis in the cellular and molecular pathogenesis of emphysema, we employed a genetic complementation strategy using emphysematous gp130F/F mice displaying hyperactivation of endogenous Stat3 that were interbred with mice to impede Stat3 activity. Resected human lung tissue from patients with COPD and COPD-free individuals was also evaluated by immunohistochemistry. Genetic reduction of Stat3 hyperactivity in gp130F/F: Stat3 −/+ mice prevented lung inflammation and excessive protease activity; however, emphysema still developed. In support of these findings, Stat3 activation levels in human lung tissue correlated with the extent of pulmonary inflammation but not airflow obstruction in COPD. Furthermore, COPD lung tissue displayed increased levels of IL-6 and apoptotic alveolar cells, supporting our previous observation that increased endogenous IL-6 expression in the lungs of gp130F/F mice contributes to emphysema by promoting alveolar cell apoptosis. Collectively, our data suggest that IL-6 promotes emphysema via upregulation of Stat3-independent apoptosis, whereas IL-6 induction of lung inflammation occurs via Stat3. We propose that while discrete targeting of Stat3 may alleviate pulmonary inflammation, global targeting of IL-6 potentially represents a therapeutically advantageous approach to combat COPD phenotypes where emphysema predominates.

scholarly journals Whole transcriptome analysis of human lung tissue to identify COPD-associated gene

2020 ◽  
Author(s):  
Qiuyu Li ◽  
Yizhang Zhu ◽  
Aiyuan Zhou ◽  
Yuxin Yin
Keyword(s):  
Lung Tissue ◽  
Human Lung ◽  
Tissue Expression ◽  
Chronic Obstructive ◽  
Human Lung Tissue ◽  
Obstructive Pulmonary Disease ◽  
Copd Patients ◽  
Matrix Organization ◽  
Whole Transcriptome Analysis ◽  
Whole Transcriptome

Abstract Identification of the dysfunctional genes in human lung from patients with Chronic obstructive pulmonary disease (COPD) will help up to understand the pathology of this disease. Here, using transcriptomic data of lung tissue for 91 COPD cases and 182 matched healthy controls from the Genotype-Tissue Expression (GTEx) database. Employing a stringent model controlling for known covariates and hidden confounders, we identified 1,359 significant differentially expressed genes (DEG) with 707 upregulated and 602 downregulated respectively. We evaluated the identified DEGs in an independent microarray cohort of 219 COPD and 108 controls, demonstrating the robustness of our result. Functional annotation of COPD-associated genes highlighted the activation of complement cascade, dysregulation of inflammatory response and extracellular matrix organization in the COPD patients. In addition, we identified several novel key-hub genes involved in the COPD pathogenesis using a network analysis method. In summary, our study represents the comprehensive analysis of gene expression on COPD with the largest sample size providing great resource for the molecular research in the COPD community.

Effect of Benoxaprofen on Release of Slow-Reacting Substances from Human Lung Tissue In Vitro

1982 ◽  
Vol 63 (2) ◽  
pp. 219-221 ◽  
Author(s):  
V. Y. Lee ◽  
J. Margaret Hughes ◽  
J. P. Seale ◽  
Diana M. Temple
Keyword(s):  
Lung Cancer ◽  
Lung Tissue ◽  
Human Lung ◽  
Calcium Ionophore ◽  
Inhibitory Effects ◽  
Human Lung Tissue ◽  
Normal Human ◽  
Clinical Asthma

1. Macroscopically normal human lung tissue was obtained from operative specimens removed for lung cancer and challenged with antigen or calcium ionophore. The release of histamine and slow-reacting substances was measured by fluorimetric and bioassay techniques respectively. 2. Benoxaprofen, a drug with inhibitory effects on the lipoxygenase and cyclo-oxygenase pathways, caused a dose-related reduction of release of slow-reacting substances without affecting histamine release. 3. These results with human lung tissue in vitro suggest that benoxaprofen may be used to investigate the role of slow-reacting substances in experimental and clinical asthma.

scholarly journals Whole transcriptome analyis of human lung tissue to identify COPD-associated gene

2020 ◽  
Author(s):  
Yizhang Zhu ◽  
Qiuyu Li ◽  
Aiyuan Zhou ◽  
Alexandra C. Racanelli ◽  
Augustine M.K. Choi ◽  
...  
Keyword(s):  
Chronic Obstructive Pulmonary Disease ◽  
Pulmonary Disease ◽  
Lung Tissue ◽  
Human Lung ◽  
R Package ◽  
Tissue Expression ◽  
Chronic Obstructive ◽  
Common Disease ◽  
Human Lung Tissue ◽  
Obstructive Pulmonary Disease

Abstract Background: Chronic obstructive pulmonary disease (COPD) is a common disease characterized by persistent respiratory symptoms and airflow restriction. The mechanisms underlying pathogenesis in COPD are still poorly understood. Identification of the dysfunctional genes in human lung from patients with Chronic obstructive pulmonary disease (COPD) will help up to understand the pathology of this disease. To identify the dysfunctional genes in human lung from patients with Chronic obstructive pulmonary disease (COPD). We used transcriptomic data of lung tissue for 91 COPD cases and 182 matched healthy controls from the Genotype-Tissue Expression (GTEx) database. We employed a stringent model controlling for known covariates and hidden confounders. DESeq2 R package (v1.20.0) was used to test for differential expression.Results: We identified 1,359 significant differentially expressed genes (DEG) with 707 upregulated and 602 downregulated respectively. We evaluated the identified DEGs in an independent microarray cohort of 219 COPD and 108 controls, demonstrating the robustness of our result. Functional annotation of COPD-associated genes highlighted the activation of complement cascade, dysregulation of inflammatory response and extracellular matrix organization in the COPD patients. In addition, we identified several novel key-hub genes involved in the COPD pathogenesis using a network analysis method.Conclusion: In summary, our study represents the comprehensive analysis of gene expression on COPD with the largest sample size, providing great resource for the molecular research in the COPD community.

scholarly journals Self-organized stem cell-derived human lung buds with proximo-distal patterning and novel targets of SARS-CoV-2

2021 ◽  
Author(s):  
E.A. Rosado-Olivieri ◽  
B. Razooky ◽  
H.-H. Hoffmann ◽  
R. De Santis ◽  
C.M. Rice ◽  
...  
Keyword(s):  
Stem Cells ◽  
Lung Tissue ◽  
Neutralizing Antibodies ◽  
Human Lung ◽  
Cell Type ◽  
Alveolar Cells ◽  
Human Lung Tissue ◽  
Alveolar Tissue

AbstractSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of the global COVID-19 pandemic and the lack of therapeutics hinders pandemic control1–2. Although lung disease is the primary clinical outcome in COVID-19 patients1–3, how SARS-CoV-2 induces tissue pathology in the lung remains elusive. Here we describe a high-throughput platform to generate tens of thousands of self-organizing, nearly identical, and genetically matched human lung buds derived from human pluripotent stem cells (hPSCs) cultured on micropatterned substrates. Strikingly, in vitro-derived human lung buds resemble fetal human lung tissue and display in vivo-like proximo-distal coordination of alveolar and airway tissue differentiation whose 3D epithelial self-organization is directed by the levels of KGF. Single-cell transcriptomics unveiled the cellular identities of airway and alveolar tissue and the differentiation of WNThi cycling alveolar stem cells, a human-specific lung cell type4. These synthetic human lung buds are susceptible to infection by SARS-CoV-2 and endemic coronaviruses and can be used to track cell type-dependent susceptibilities to infection, intercellular transmission and cytopathology in airway and alveolar tissue in individual lung buds. Interestingly, we detected an increased susceptibility to infection in alveolar cells and identified cycling alveolar stem cells as targets of SARS-CoV-2. We used this platform to test neutralizing antibodies isolated from convalescent plasma that efficiently blocked SARS-CoV-2 infection and intercellular transmission. Our platform offers unlimited, rapid and scalable access to disease-relevant lung tissue that recapitulate key hallmarks of human lung development and can be used to track SARS-CoV-2 infection and identify candidate therapeutics for COVID-19.

scholarly journals Human lung extracellular matrix hydrogels resemble the stiffness and viscoelasticity of native lung tissue

2020 ◽  
Vol 318 (4) ◽  
pp. L698-L704 ◽  
Author(s):  
R. H. J. de Hilster ◽  
P. K. Sharma ◽  
M. R. Jonker ◽  
E. S. White ◽  
E. A. Gercama ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Lung Tissue ◽  
Viscoelastic Properties ◽  
Human Lung ◽  
Chronic Obstructive Lung Disease ◽  
Chronic Obstructive ◽  
Human Lung Tissue ◽  
Native Tissue ◽  
Maxwell Element ◽  
Chronic Lung Diseases

Chronic lung diseases such as idiopathic pulmonary fibrosis (IPF) and chronic obstructive pulmonary disease (COPD) are associated with changes in extracellular matrix (ECM) composition and abundance affecting the mechanical properties of the lung. This study aimed to generate ECM hydrogels from control, severe COPD [Global Initiative for Chronic Obstructive Lung Disease (GOLD) IV], and fibrotic human lung tissue and evaluate whether their stiffness and viscoelastic properties were reflective of native tissue. For hydrogel generation, control, COPD GOLD IV, and fibrotic human lung tissues were decellularized, lyophilized, ground into powder, porcine pepsin solubilized, buffered with PBS, and gelled at 37°C. Rheological properties from tissues and hydrogels were assessed with a low-load compression tester measuring the stiffness and viscoelastic properties in terms of a generalized Maxwell model representing phases of viscoelastic relaxation. The ECM hydrogels had a greater stress relaxation than tissues. ECM hydrogels required three Maxwell elements with slightly faster relaxation times (τ) than that of native tissue, which required four elements. The relative importance (Ri) of the first Maxwell element contributed the most in ECM hydrogels, whereas for tissue the contribution was spread over all four elements. IPF tissue had a longer-lasting fourth element with a higher Ri than the other tissues, and IPF ECM hydrogels did require a fourth Maxwell element, in contrast to all other ECM hydrogels. This study shows that hydrogels composed of native human lung ECM can be generated. Stiffness of ECM hydrogels resembled that of whole tissue, while viscoelasticity differed.

The Role of Cytokines in Allergic Inflammation in Human Lung Tissue

2006 ◽  
Vol 117 (2) ◽  
pp. S254
Author(s):  
L.R.C. Barnicott ◽  
T. Hackett ◽  
J.A. Warner
Keyword(s):  
Lung Tissue ◽  
Human Lung ◽  
Allergic Inflammation ◽  
Human Lung Tissue
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